Treatment of thrombosis

ABSTRACT

Pharmaceutical composition containing therapeutically active 3(parafluorobenzyloxy) benzoic acid successfully used in the treatment of thrombosis.

United States Patent [191 Malen et al.

[ Oct. 9, 1973 I TREATMENT OF THROMBOSIS [75] Inventors: Charles Malen,Fresnes Village;

Bernard Danree, St-Germain-en-Laye Village; Pierre Desnoyers,Fontenay-aux-Roses Village, all of France [73] Assignee: Science Unionet Cie, Societe Francaise de Recherche Medicale, Suresnes, France [22]Filed: Dec. 7, 1970 [21] Appl. No.: 95,957

[30] Foreign Application Priority Data Dec. 16, 1969 Great Britain61,279/69 [52] U.S. Cl 424/317, 260/473 R, 260/520, 424/329 [51] Int. ClA6lk 27/00 [58] Field of Search 424/317; 260/519,

OTHER PUBLICATIONS Schueler, Molecular Modification in Drug DesignAdvances in Chem. Series 45, ACS, 1964 p. ii, 221-222. Chem. Abs., Vol.73, 1970 No. 56088j Chem. Abs., Vol. 57, 1962 pg. l4378d PrimaryExaminer-Albert T. Meyers Assistant Examiner-A. P. FagelsonAttorney-Gordon W. Hueschen and Talivaldis Cepuritis [5 7] ABSTRACTPharmaceutical composition containing therapeutically active3-(parafluorobenzyloxy) benzoic acid successfully used in the treatmentof thrombosis.

2 Claims, No Drawings TREATMENT OF THROMBOSIS The present inventionprovides a new pharmaceutical preparation comprisingB-(para-fluorobenzyloxy) benzoic acid of formula I COOH or aphysiologically tolerable salt thereof, in admixture or conjunction witha pharmaceutically suitable carrier.

The compound of formula I is known and may be prepared by a method knownper se which comprises the reaction of a benzyl halide of the generalformula is saponified.

The reaction of the derivatives 11 and III may be carried out in asuitable solvent, such, for example, as an aliphatic alcohol, an ether,a ketone, a hydrocarbon, an aliphatic nitrile, nitromethane,dimethylformamide or dimethylacetamide, at a temperature within therange of from 20 to 150 C, in the presence of an acceptor for thehydrohalic acid formed during the reaction. This acceptor may be analkali or alkaline earth metal salt of carbonic acid, such, for example,as sodium or potassium carbonate.

3-(para-fluorobenzyloxy) benzoic acid may be converted into additionsalts with mineral or organic bases such, for example, as alkaline oralkaline earth metals hydroxides, primary, secondary and tertiaryamines, such as mono-, diand triethylamines, and heterocyclic basessuch, for example, as piperazine, piperidine, morpholine, etc Thesesalts are also included in the present invention.

The compound of formula I and its physiologically tolerable saltspossess valuable pharmacological and therapeutic properties, especiallythrombolytic and f1- brinolytic properties, and decrease theplateletstickiness and aggregation and the capillary permeability.

The thrombolytic activity was studied in vitro by the method of VonKaulla (Thromb. Diath. Haem. 5, 489 (1961)) on the standard blood clot.It was observed that the product provokes the lysis of the clot at 0,03to 0,02 molar concentrations, corresponding to concentrations between9,6 and 6,4 mg/ml.

The same activity was demonstrated in vivo by the method of Roschlau(Can. J. Biochem. Phys. 40, 1819 (1962)). 500 mg/hour of the productperfused for 6 hours in the dog, permit the dissolution of the arterialthrombus in percent of the cases.

A similar effect may be observed in vivo by the method of S. Wessler (J.Clin. Invest. 34, 647 (1955)).At the dose of 25 mg/kg i.v., the compoundinhibits the thrombosis in the rabbits vena jugularis provoked byinjection of a heterologous serum.

When administered orally at the dose of mg/kg in rat, the compounddecreases to 48 percent the euglobulin lysis time 60 minutes afteradministration (Von Kaulla Am. J. Clin. Path. 29 104 (1958)).

The compound decreases also the capillary permeability. By the test ofAmbrose and Eds (J. Pharm. Exp. Therap. 90, 359 (1947)), it was observedthat it increases to 3, 5 times the delay of appearance of thecoloration on the rabbits depilated abdominal skin of 2 cm3 of Trypanblue at 1 percent, when administered intraperitoneally at 100 mg/kg.

By using the Salzman method (J. Lab. Clin. Med. 62, 724 (1963)), it wasobserved that the product decreases by l 1 percent the plateletstickiness 1 hour after the administration of 100 mg/kg P.O.

The effect of the compound on the platelet aggregation was evidenced bythe photometric technique of Born and OBrien, modified by Sinakos andCaen (Rev. Fr. Et. Clin. Biol. 11, 538 (1966)). A concentration of 500to 750y/ml of the compound inhibits by 100 percent the plateletaggregation provoked by thrombine in the rat and rabbit plasma.

The toxicity of the compound shows a LD of 300 mg/kg i.v. and 1500 mg/kgP.O. in mice.

The compound may be used successfully in therapy, especially in thetreatment of thrombosis in a living animal body afflicted with the same.

The compound of formula I, or a physiologically tolerable salt thereof,can be administered especially by intravenous route in form of solutionsin distilled water, isotonic sodium chloride or glucose. The doses maybe of 5 to 50 mg/kg, preferably 5 to 10 mg/kg/hour for 3 to 6 hours. Thepharmaceutical dosage unit form contains from 100 to 1000 mg. of theactive ingredient.

The following examples illustrate the invention. The melting points wereobtained on a Kofler block (K) or a Kofler heater under a microscope(M.K.).

EXAMPLE 1 3-(para-fluorobenzyloxy) benzoic acid COOH 34.5 g (0.25 mole)of dry and powdered potassium carbonate were added to a solution of 6.9g (.0.05 mole) of meta-hydroxybenzoic acid in 60 ml of dimeth;ylformamide. The suspension was heated up to 100 C and 2l.5 g (0.12mole) of para-fluorobenzyl chloride were dropped, while stirring.

The mixture was maintained at lOO C, while stirring, for one hour thenit was cooled and diluted with 200 ml of water. The white precipitatewas suctioned off, washed with water and dried. 20.5 g ofparafluorobenzyl 3-(parafluorobenzyloxy) benzoate, melting (K) at 74-75C, were obtained.

This ester was saponified with 70 ml of a percent hydroalcoholicsolution of potassium hydroxide, while refluxing for 2 hours.

The para-fluorobenzyl alcohol was extracted with ether and the aqueousalkaline phase was acidified with a 2 N solution of hydrochloric acid.The so-obtained acid was suctioned off, washed with water and dried. l1.2 g of S-(parafluorobenzyloxy) benzoic acid, melting (M.K.) at 150-152C, were obtained.

5.6. of diethylamine were added to a suspension of 8 g of3-(parafluorobenzyloxy) benzoic acid in 70 ml of ethanol. minutes later,the ethanol was evaporated under vacuum and the residue wasrecrystallized in a mixture of .20 ml of cyclohexane and 5 ml ofbenzene.

6 g "of diethylarnmonium B-(para-fluorobenzyloxy) benzoate, melting(M.K.) at 8 l-83 C, were obtained.

EXAMPLE 2 Diethylammonium 3-( para-fluorobenzyloxy) benzoate l g Glucose25 8 Bidistilled water, q.s.p. 500 g

2. The method of Claim 1, wherein the amount administered is 5 to 50mg/kg and the period of administration is up to 6 hours.